Quinobenzoxa(or thia)zepin-3-ones

ABSTRACT

WHEREIN X, Y, R, n, n&#39;&#39; and A are as defined hereinafter. These compounds are useful as antifungal agents and antibacterial agents.   Quinobenzoxa(or thia)zepin-3-one derivatives are provided having the structures

United States Patent 1 Yale et al.

[ Sept. 18, 1973 QUINOBENZOXA(OR THIA)ZEPlN-3-ONES [75] lnventors: Harry Louis Yale; Rarnesh B.

Petigara, both of New Brunswick,

[73] Assignee: E. R. Squibb & Sons, Inc.,, New

York, NY.

[22] Filed: Dec. 9, 1970 [21] Appl. No.: 96,614

[56] I ReierelieesCited OTHER PUBLICATIONS Fieser & Fieser, Reagents For Organic Synthesis, Vol. I, Wiley Publishers, Pages 128, 215-219 QD 262,.F5

Primary Examiner-Alan L. Rotman Attorney-Lawrence S. Levinson, Merle J. Smith and Donald J. Perrella [5 7] ABSTRACT Quinobenzoxa(or thia)zepin-3-one derivatives are provided having the structures A-CH;

A-CH1 C H N wherein X, Y, R, n, n' and A are as defined hereinafter. These compounds are useful as antifungal agents and antibacterial agents.

6 Claims, No Drawings 1 QUINOBENZOXA(OR THIA)ZEPIN-3-ONES The present invention relates to quinobenzoxa(or thialzepin-3-ones derivatives of the structure wherein X and Y are the same or different and can be halogen, trifluoromethyl, lower alkyl, lower alkylmercapto, lower alkyloxy, cyano, or di-lower alkylsulfamoyl, R is lower alkyl, halogen or hydrogen, n is O, 1 or 2 and n is 0, l or 2 and A is 0, S, S or S0 The term lower alkyl as employed herein includes both straight and branched chain radicals of up to and including eight carbon atoms, for instance, methyl, ethyl, propyl, isopropyl, butyl, s'butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like. The lower alkyl group can include substituents such as aryl.

The term halogen includes F, Cl or Br.

The lower alkylmercapto groups contain up to 8 carbon atoms and include methylmercapto, ethylmercapto, propylmercapto and mercapto radicals containing any of the lower alkyl groups mentioned hereinbefore.

The terms lower alkyloxy and lower alkoxy are interchangeable and refer to groups containing up to eight carbon atoms and which include any of the lower alkyl groups mentioned hereinbefore attached to an oxygen atom.

In the above Formulae l and II, each of the carbocyclic aromatic rings can include 0, l to 2 substituents, other than hydrogen. The nature and position of the substituents in the starting materials will determine which isomer, Type I and/or Type II, is obtained.

As will be seen hereinafter, the compounds of the invention are prepared from starting materials of the structure Where in the starting material Ila, n is l or 2 and X includes a strongly electronegative group like trifluorodirected to the 4 position so that the type II isomer is subsequently formed. However, where X is an ortho para orienting group like halogen, especially chlorine, and n is l or 2 and at least one halogen is at the 7- position of starting material Ila, or Y is lower alkyl, lower alkyloxy, or lower alkylmercapto at any position or strongly electronegative group at a position other than 3 and n' is O, a mixture of the Type I and Type II isomers is obtained.

Where in the starting material Ila, n' is l or 2 and Y includes a strongly electronegative group like trifluoromethyl, cyano or di-lower alkylsulfamoyl at the 3- position, and n is O or X is a substituent at a position other than 7 in the starting material, cyclization is directed to the 6-position so that the Type I isomer is subsequently formed.

Where in the starting material Ila, n is l or 2 and Y includes an ortho-para orienting substituent at the 3- position, and n is O or X is a substituent at a position other than 7 in the starting material, cyclization is directed to the 6-position so that the Type I isomer is subsequently formed.

Where n and n' are 0, that is where there are no substituents on either aromatic ring, the Type I isomer is obtained, that is m, tics.

' Where the starting material does notinclude substituents at the 3 and/or 7 positions, but does include substituents such as lower alkyl, lower alkyloxy, or lower alkylmercapto at the 1,2,8 and/or 9 positions, the Type l isomer is obtained.

Where the starting material does not include substituents at the 3 and/or 7 positions, but does include strongly electro-negative groups at the 1 and/or 9 positions, the Type I isomer is obtained. However, where the starting material unsubstituted at the 3 and/or 7 positions includes a strongly electronegative group at the 2 and/or 8 positions, then a mixture of the Type I and Type II isomers, or either Type II or Type I, respectively, is obtained.

Where X represents a strongly electronegative group like trifluoromethyl, cyano or di-llower alkylsulfamoyl and n is l or 2 at least one X being at the 7-position of the starting material and Y is lower alkyl, lower alkyloxy or lower alkylmercapto at any position or any of the above strongly electronegative groups at a position other than 3 in the starting material and n is 0, l or 2, the Type' II isomer is obtained.

Where X is lower alkyl, lower alkyloxy, or lower alkylmercapto and n is 0, l or 2 and ,Y is halogen, trifluoromethyl, cyano or di-lower alkylsulfamoyl, and n is l or 2 at least one Y being at the 3-position of the starting material, the Type I isomer is obtained. In this case, X can be trifluoromethyl or other strongly electronegative group so long as it is not in the 7-position of the starting material as will be seen hereinafter.

Where X is lower alkyl, lower alkyloxy, or lower alkylmercapto, and n is 1 or 2 and n in (Y),, is O, the

Type I isomer is obtained.

Where Y is lower alkyl, lower alkyloxy, or lower alkylmercapto and n' is l or 2 and the n in (X),, is O, the Type II isomer is obtained.

Where both X and Y represent lower alkyl, lower alkoxy and/or lower alkylmercapto, at least one of said groups being at the 3 and 7 positions of the starting material, the Type I isomer is obtained.

Examples of compounds falling within the present invention include, but are not limited to, the following:

The symbol A in the formulae below represents -O-, -S-, -SO- and -SO,-; each formula therefore, in essence, representing four species.

s. A-C

9. A oi;

Q /N0z 00am CH3 0 N 15 Q 10. A A-CI-l; iv A 20 0 F 0 SCaH1 CH N 11. ACH:

CF: Q

1 2. Arch,

L C1 40 CH m CJHOOl C) I 14. H A-oii,

(l 5 l tl,.- l 1 (lll 01@ -Br on A) The compounds of Formulae l and ll of the invention can be obtained by reacting the corresponding 1,2- dihydroquinobenzoxa(or thia)zepin-3-one of the structure ACH;

I L, Y Y

in non-aqueous solvent such as dioxane, aromatic hydrocarbons such as benzene, toluene or xylene or alcohols such as t-butanol, with 2,3-dichloro-5,6-dicyanop-benzoquinone (DDQ) in a molar ratio of III or IVzDDQ within the range of from about 0.5:1 to about 0.7:1, at a temperature within the range of from about 80 to about 130 C.

The starting materials of the Formulae lll and/0r lV can be prepared by reacting a compound of the structure wherein X, Y, n, n, A and R are as defined hereinbefore, with a phosphorus pentahalide, such as phosphorous pentachloride, in a molar ratio of Vzpentahalide of within the range of from about 0.9: l to about 1:1, in the absence of oxygen, and in the presence of an inert solvent, such as benzene, toluene, xylene, pentane, hexane, etc., at a temperature within the range of from about 0 to about 10 C, to form an acyl halide of the structure The acyl halide V] is reacted with anhydrous stannic chloride in a molar ratio of acyl halide Vlzstannic chloride within the range of from about 0.421 to about 0.5:1, at a temperature within the range of from about 20 to about 30 C. to form the Formula Ill and/or IV compounds depending upon the nature and the position of the X and Y substituents.

A-CH;

( )n (Y)n' r Y III A-CHg l L, IV E The compounds of Formulae llI and/or lV can also be prepared by reacting the starting material vn A-crr,

( )n )n CH\ITJ/R 011 cm drrcoon with trifluoroacetic anhydride or phosphorous pentoxide, in a molar ratio of Vllztrifluorbacetic anhydride or phosphorous pentoxide of within the range of from about 0.9: l to about 1:1, in the presence of an inert solvent such as benzene, toluene, xylene, pentane, hexane, etc., at a temperature within the range of from about 10 to about C.

Compounds of the structure I and Il wherein A is S0 or SO, can be prepared as follows:

Compounds of the structures Ill or IV wherein A is S are treated with an oxidizing agent like H O, in an alcohol solvent or perbenzoic acid I or mchloroperbenzoic acid in a solvent like chloroform to give sulfoxides of the structures VIII or IX which are converted to the Formulae I and II compounds as described herein.

Compounds of Formulae I and II wherein A is 80 can be formed by treating III or IV (wherein A is S) with an oxidizing agent like H O, in formic or acetic acid to give sulfones of the structures X and XI, respectively sorcn, (X) n @0011 X11 A-CH:

with a nitrile of the structure XIII CHnO-CN wherein R is hydrogen, lower alkyl or halogen (e.g. acrylonitrile, Z-methylacryllonitrile, 2- isopropylacrylonitrile, 2-pentylacry1onitrile, 2- chloroacrylonitrile, 2-bromacrylonitrile, 2-

fluoroacrylonitrile and the like) to yield compounds of Formula XIV wherein n, n, R, A, S and Y are as defined herein.

This reaction is carried out by employing an excess of the nitrile as the solvent. The temperature utilized in the reaction can be varied from about 0 to about 100 C. with the preferred range being between about 0 and about C. This reaction proceeds expeditiously when a small amount (up to about 1 percent) of a strong base like sodium hydroxide, sodium methoxide, potassium t-butoxide, or benzyl trimethyl-ammonium hydroxide (Triton B) is used as the catalyst.

Another procedure for preparing compounds of Formula VII is to treat the compounds of structure XIV with alcoholic hydrogen halide, such as hydrogen chloride in methanol, ethanol, and so forth, at room temperature whereby esters of the structure XV are formed.

wherein R is lower alkyl.

By saponifying compound XV with an alkali metal hydroxide, e.g., sodium hydroxide, lithium hydroxide, and so forth, the desired carboxylic acids of structure XIV can be recovered.

Examples of compounds of Formula XII where A is S are set out in U.S. Pat. Nos. 3,188,321 and 3,188,322.

Examples of compounds of Formula VII where A is O or S can be found in U.S. Pat. Nos. 3,069,432, and 3,452,046 and in a paper entitled Novel Polycyclic I-Ieterocycles, by Yale et a1, Med. Chem. 13, 713 (1970).

Examples of compounds of Formula XII wherein A is S0 or S0 can be found in the above mentioned paper by Yale et a1.

Furthermore, compounds of Formula XII wherein A is so can be formed by heating a compound of the structure XVI S-CH:

in the presence of potassium carbonate, Cu bronze, and a suitable solvent and treating the product with, ether to give compounds of the structure and treating compound XVII with m-chloroperbenzoic acid in the presence of chloroform and then treating with ether to give a compound of the structure XVIII XVIII so-om which can be treated with alcohol such as ethanol and base such as aqueous sodium hydroxide to form a compound of the structure Compounds of Formula XII wherein A is S can be formed by treating compounds of the structure XX S CH2 with an oxidizing agent such as hydrogen peroxide in the presence of formic acid to form a compound of the structure XXI "56,1614,

(X) n (Y) n and treating XXI with an alcohol such as ethanol and base such as aqueous sodium hydroxide to form a compound of the structure vention include, but are not limited to, the following wherein A is O, S, S0 or S0 CH N l CH2CHzCOOH HiCHzC O OH 1i CH N C H dmcmc 0 OH A-CH1 CH N c monsoon A-CH;

No,s CH N CH3 CH HqCHCOOH A-CH: G CHI FJC 0 CH:

CH N CH JHICHC O OH I A-CH; I NC 0 J-00,115 OH\III CH C HgCHzCOOH A-CH: 0 0 NC- -SCHa OH I? OH CIhCHCOOH CH\N H CH COOH FQC a a CH N/ on JJII CIhCOOll CH N C CHgCHzG O OH A-CH2 C) C) $021I CH N on CHzCHzC O OH A-on, I on N on Uzi- 3H2 1-1 01138 CH O CH;

CH N

l CHaCI-IaC O OH ON l A cm 0 o ON CH 1y CH crncmooon A-CH1 fill 021150 c F.

on N/ on HICHiC O OH I A-CT-Iz Cl C N 01 0 O 2 5 CH N CH l CH CHzC O O H CH: CH:

1 A-CH: on crn Q C) CH N o HzCI-hCOOH L (Yn' on l N o l CH N wherein R is halogen or lower alkyl are novel intermediates. Examples of such compounds correspond to the examples of the dehydro compounds of the invention set out herein wherein R is other than hydrogen.

The new compounds of Formulae l and I] are useful as antimicrobial agents and may be used to combat infections in animal species, such as mice, rats, dogs, guinea pigs and the like, due to organisms such as Trichomonas vaginalis, Trichomonas foetus, Staphyloccocus aureus, Salmonella schottmuelleri, Klebsiella pneumoniae, Proteus vulgaris, Escherichia coli, C. albicans or Trichophyton mentagrophytes. For example, a compound or mixture of compounds of Formulae I and H may be administered orally to an infected animal, e.g., to a mouse, in an amount of about 5 to 25 mg. per kg. per day in 2 to 4 divided doses. These may be conventionally formulated in a tablet, capsule or elixir containing about 10 to 250 mg. per dosage unit, by compouding the active substance or substances with the conventional excipient, vehicle, binder, preservative,

flavor, etc., as called for by accepted pharmaceutical practice. They may also be applied topically, e.g., to dermatophytosis in a guinea pig, in a lotion, salve or cream at a concentration of about 0.1 to 3 percent by weight.

They may also be used as surface disinfectants. About 0.01 to 1 percent by weight of any of these substances may be dispersed on an inert solid or in a liquid such as water and applied as a dust or spray. They may be incorporated also, for example, in a soap or other cleansing agent, e.g., a solid or liquid detergent, detergent composition, for example, in general cleaning, in cleaning dairy barns or equipment or cleaning food handling or processing equipment.

The following examples are illustrative of the invention. All temperatures are on the Centigrade scale.

EXAMPLE 1 3H,8H-quino[ 1,8-a,b] [4,1 ]benzoxazepin-3-one A. 5,1 l-Dihydrodibenz[b,e][ l ,4]oxazepine-5- propionic acid A suspension of 30.4 g of 5,1 l-dihydrodibenz[- b,e][l,4]-oxazepine in ml of acrylonitrile is cooled to O5. To this is added with efficient stirring and cooling 0.9 ml of Triton B. The suspension becomes homogeneous and a red solution results with the rise of temperature to 10. The reaction mixture is allowed to come to room temperature and then refluxed for one hour with stirring. The excess of acrylonitrile is removed by known means, water is added, and the solid is filtered. The solid is dried, powdered, and extracted with five 400 ml portions of diethyl ether. The diethyl ether extracts are dried and concentrated to a volume of 250 ml. The white crystalline compound is filtered. The filtrate is again concentrated and the resulting solid is filtered and found to melt to about l38-139.5, and is identified as ,1 ldihydrodibenz[b,e][ 1 ,4]oxazepine-5-propionitrile.

The 5,1 l-dihydrodibenz[b,e][1,4]oxazepine-5- propionitrile, 5.0 g, is dissolved in 80 ml of dry dioxane and to this 55 ml of 30 percent methanolic hydrogen chloride is added. The solution is stirred for 72 hours, 2 ml of water added, and then concentrated to 30 ml, filtered, and the filtrate concentrated to give 5,1 1- dihydrodibenz[b,e][ 1,4]oxazepine-5-propionic acid, methyl ester, mp about 7072.

A solution of the methyl ester, 5 g., 440 ml of methanol, and 1.1 g. of potassium hydroxide in 60 ml of water is refluxed for 4 hours, and concentrated in vacuo. The residue is dissolved in 120 ml of water and the solution acidified to give 5,1l-dihydro[b,e][1,4]oxazepine-5- propionic acid mp about 203-205. I

B. l,2-Dihydro-3H,8H-quino[ 1,8-a,b] [4,1 ]benzoxazepin-3-one In a 500 ml flask equipped with stirring bar, thermometer, nitrogen inlet, dropping funnel and CaCl guard tube, is suspended 10.8 g. of 5,11- dihydrodibenz[b,e][ l ,4]oxazepine-5-propionic acid in 220 ml of C l-1,. This is cooled to and to it is added a solution of 9.5 g. of PC]; in 50 ml of benzenein 45 minutes. The reaction mixture is stirred for 1.5 hr. at room temperature. To the resulting solution, 5.5 g. of sodium hydrosulfite is added and stirred for minutes. The reaction mixture is filtered and the filtrate is concentrated in vacuo to yield a liquid residue. The residue is triturated with 70 ml of petroleum ether to give a yellow solid, which is filtered. Of the acid chloride residue (9.6 g.), 8.6 g. are dissolved immediately in 220 ml of benzene.

The above solution of 8.6 g of the acid chloride in 220 ml of benzene is placed in a flask equipped with a stirrer, a dropping funnel, and a reflux condenser guarded with a CaCl, tube. To this, while stirring, is added dropwise, a solution of 9.0 ml of anhydrous SnCl, is 50 ml of benzene. A viscous red complex forms which turns to violet towards the end of the addition. The reaction mixture is stirred for 1 hour and then 600 ml of ether is added. To this, ml of cone. HCl and 150 ml of distilled 11 0 are added and the mixture stirred vigorously for 1 hour. The organic phase is separated, washed, filtered, and solvent removed and the residue is extracted successively with 300, 200, and 200 ml portions of boiling cyclohexane. The combined cyclohexane extracts are concentrated to 75 ml to give 2.9 g of product, mp about 1 16-118.

C. 3H,8H-Quino[ 1 ,8-a,b][4,l lbenzoxazepin-B-one To 2.5 g of l,2-dihydro-3l-l,8l-l-quino[ l,8-a,b][4,l benzoxazepin-B-one in 50 ml of anhydrous o-xylene is added 2.8 g of 2,3-dichloro-5,6-dicyano-pbenzoquinone and the mixture is heated under flux for 24 hours. The mixture is then filtered and the filtrate concentrated to dryness in vacuo. The residue is dissolved in 300 ml of a mixture of methylene dichloride and ether (1:3) washed successively with dilute alkali, with water and with saturated sodium chloride solution, dried and filtered. The filtrate is concentrated to dryness in vacuo to give 2.1 gof a yellow solid which on recrystallization from ethanol yields a yellow solid, mp about l65l67.

EXAMPLE 2 l l-Chloro-3l-l,8H-quino[ l,8-a,b][4,l ]benzoxazepin- 3-one A. 3-Chloro-5,l ldihydrodibenz[b,e][ 1 ,4]oxazepine-5-propionic acid A suspension of 24.4 g of 3-chloro-5,1l dihydrodibenz [b,e][ 1,4]oxazepine in 55 ml of acrylonitrile is cooled to 0-5. To this is added with efficient stirring, and cooling, 0.3 ml of Triton B, pausing after each drop of addition. The temperature rises slowly from 3 to 14 and then rapidly to 45 within 5 minutes with the formation of red colored clear solution. The mixture is cooled to 5-l0, stirred for 5 minutes, allowed to come to room temperature and then slowly heated to reflux temperature. After 1 hour heating under reflux, the excess of acrylonitrile is removed in vacuo. The residue is extracted with 3-3 50 ml portions of diethyl ether, the combined diethyl ether extracts are treated with 3.0 g of Darco and 1.0 g of l-lyflo, filtered; the filtrate is dried, and concentrated to give 31.6 g of 3-chloro-5,l l-dihydrodibenz [b,e][ 1,4] oxazepine-S-propionitrile, b.p. about 2002l0 (0.2 mm).

The 3-chloro-5,l ldihydrodibenz[b,e 1,4]oxazepine-5-propionitrile, 71.10 g, is dissolved in 1,200 ml of dry dioxane and to this 800 ml of 30 percent methanolic hydrogen chloride is added. The solution is stirred for 72 hours, 30 ml of 11,0 is added, the mixture is stirred for 0.5 hour, concentrated in vacuo to 400 ml, filtered, and the filtrate concentrated to dryness in vacuo. The residue s0- lidifies on keeping to yield 3-chloro-5,l1- dihydrodibenz[b,e][ 1,4]oxazepine-5-propionic acid, methyl ester.

The 3-chloro-5 1 1 dihydrodibenz[b,e][ 1,4]oxazepine-5-propionic acid, methyl ester, 25.4 g, is dissolved in 2,200 ml of MeOl-l and to this 5.6 g of KOH dissolved in 300 ml of 11,0 is added. The solution is refluxed for 4 hours, and then is concentrated in vacuo. The residue is taken up in 600 ml of H 0, the solution is cooled, and then acidified with 2 percent aqueous HCl. The solid is filtered and dissolved in 600 ml of C l-1,. This solution is treated with Darco and then extracted with 600 ml of 2 percent aqueous NaOH solution. The extracts are treated with Darco and Hyflo, filtered and the filtrate is acidified with 2 percent aqueous HCl. The solid is filtered and recrystallized from C l-I to yield 3-chloro-5,-l ldihydrodibenz[b,e] 1 ,4]oxazepine-5-propionic acid, mp about 138-140.

B. l l-Chloro-1,2-dihydro-3H,8H-quino[ 1,8- a,b] 4,1 ]-benzoxazepin-3-one 3.7 g of 3-chloro-5,ll-dihydro[b,e][1,4]oxazepine- S-propionic acid is dissolved in 20 ml of warm benzene and the resulting colorless solution is allowed to come to 30, and to this, 1.9 ml (2.8 g) of (CF,CO) O is added dropwise. The reaction mixture is slowly heated to reflux, the reflux is maintained for 5 minutes, and the mixture is poured into 250 ml of cold water. To this, ml of benzene is added, and stirred for a few minutes. The benzene layer isseparated, washed, dried, filtered, and concentrated to dryness. The residue is re crystallized first from 2-propanol and then from cyclohexane to give 2.3 g of product, mp about l42l44.

C. l l-Chloro-3H,8H-quino[l,8-a,b][4,1]benzoxazepin-3-one To 2.85 g of ll-chloro-l,2-dihydro3l-l,8I-iquino[l,8-a,b]-[4,l lbenzoxazepin-3-one in 50 ml of t-butanol is added 3.0 g of 2,3-dichloro-5,6-dicyano-pbenzoquinone and the mixture is heated under reflux for 24 hours. The mixture is then filtered and the filtrate concentrated to dryness in vacuo. The residue is dissolved in 300 ml of a mixture of methylene dichloride and ether (1:3), washed successively with dilute alkali, with water and with saturated sodium chloride solution, dried and filtered. The filtrate is concentrated to dryness in vacuo to give 2.6 g of a yellow solid which on recrystallization from ethanol yields a yellow solid, mp about 235-238.

EXAMPLE 3 A. 5,1 l-Dihydro-7- (trifluoromethyl)dibenz[b,e][ l ,4]-thiazepine-5- propionic acid To 50.0 g of 5,1 l-dihydro-7-(trifiuoromethyl)dibenz- [b,e][ l ,4lthiazepine in 60 ml of redistilled acrylonitrile is added in 5 minutes 0.80 ml of Triton B. Subsequently, the mixture is heated for 1 hour under reflux and the product isolated by extraction with benzene to give 5,] l-dihydro-7- (trifiuoromethyl)dibenz[b,e][ 1,4]thiazepine-5- propionitrile, mp about l6l-l63.

7-(Trifluoromethyl)5 ,1 1- dihydrodibenz[b,e][ l ,4]thiazepine-S-propionitrile, 15.0 g, is dissolved in 240 ml of dry dioxane and to this 140 ml of 30 percent methanolic hydrogen chloride is added. The solution is stirred for 36 hours, 6 m] of H is added, stirred 0.5 hour, and then concentrated in vacuo to 120 ml. The solid is filtered, and the filtrate is concentrated to dryness in vacuo. The residual liquid is taken up in 200 ml of diethyl ether, treated with Darco and Hyflo, the diethyl ether solution is concentrated and the residue distilled in vacuo to give 5,11- dihydro-7-( trifluoromethyl )dibenz[ b,e][ l,4lthiazepine--propionic acid, methyl ester, b.p. about l66-168 (0.08 mm.), mp about 70.0 71.5.

7-(Trifluoromethyl-5 ,1 ldihydrodibenz[b,e][ 1 ,4]thiazepine-5-propionic acid, methyl ester, 3.15 g, is dissolved in 315 ml of methanol and to this 0.5 g of potassium hydroxide dissolved in 25 ml of water is added. The mixture is refluxed for 2.5 hours and then concentrated in vacuo. The residue is taken up in 250 ml of water and this solution is acidified with 2percent aqueous BC] to give 5,1 l-dihydro- 7-(trifluoromethyl)-dibenz[b,e][ 1,4]thiazepin-5- propionic acid, mp about 94-96.

B. 1,2-Dihydro-l 1-(trifluoromethyl)-3H,7H-quino- [8, l -c,d][ 1,5 l-benzthiazepin-3-one A solution of 6.86 g of 5,1 l-dihydro-7- (trifluoromethyl)dibenz[b,e][1,4]thiazepine-5- propionic acid in 50 ml of benzene is cooled to 5-l0. To this is added dropwise with stirring a solution of 4.6 g of PC],, in 25 ml of benzene over a period of minutes. The solution is stirred at 25 for 40 minutes and then at 40-50 for another minutes. The reaction mixture is then heated at 55 for 10 minutes, cooled to 10 and to this is added dropwise with stirring a solution of 12.0 g anhydrous SnCL, in 20 :ml of benzene. After stirring 20 minutes at 10 and 20 minutes at room temperature, ml of ether is added, followed by 10 ml of concentrated hydrochloric acid, and then 100 ml of water. After stirring vigorously for 10 minutes, the organic phase is separated, and the aqueous phase is extracted with 100 ml of ether. The combined organic extracts are washed, dried, filtered, and concentrated to dryness to give 6.9 g of residue; this is crystallized from Z-propanol to give 4.3 g of product, mp about l40-l4- 2.

To 2.5 g of l l-(trifluoromethyl)-l,2-dihydro-3H,7H- quino[8,l-c,d][ l,5]benzthiazepin--3-one in 50 ml of anhydrous dioxane is added 2.3 g of 2,3-dichloro-5,6- dicyano-p-benzoquinone and the mixture is heated under reflux for 24 hours. The mixture is then filtered and the filtrate concentrated to dryness in vacuo. The residue is dissolved in 300 ml of a mixture of methylene dichloride and ether (1:3), washed successively with dilute alkali, with water and with saturated sodium chloride solution, dried and filtered. The filtrate is concentrated to dryness in vacuo to give 2.1 g of a yellow solid which on recrystallization from ethanol yields a white crystalline product, mp about 169-471.

EXAMPLE 4 l l-(Trifiuoromethyl)-3H,7H-qu.ino[8, l c,d 1,5 ]benzthiazepin 3-one, 8-oxide To a solution of 3.35 g of (trifluoromethyl )3H,7H-quino[8, l c,d][1,5]benzthiazepin-3-one in 40 ml of CHCl is added 1.8 g of rn-chloroperbenzoic acid, and the mixture refluxed for 7 hours, cooled, and washed with 5 percent aqueous NaCO solution, followed by water, dried, and filtered. Removal of solvent gives 3.4 g of residue, which is crystallized from cyclohexane to give 1.8 g of l ,Z-dihydro-l l-(trifluoromethyl )-3H,7H- quino[ 8, 1 -c,d][ 1,5 Ibenzthiazepin-3-one, 8-oxide which is dehydrogenated as described in Example 3 to form the title compound.

EXAMPLE 5 1 l-(Trifluoromethyl)-3H,7H-quino[ 8, l c,d 1,5 ]benzthiazepine-3-one, 8,8-dioxide To a suspension of 3.35 g of 1,2-dihydro-l l- (trifluoromethyl)-3H,7H-quino[ 8, lc,d][1,5]benzthiazepin-3-one in 15 ml of 98-100 percent formic acid is added dropwise 5 ml of 30 percent H 0 while stirring at 60. The reaction mixture is heated at 60 for 4 hours, and concentrated to dryness in vacuo. The residue is crystallized from toluene to give 2.3 g of l,2-dihydro-l l-(trifluoromethyl)-3H,7H- quino[ 8, l -c,d][ 1,5 lbenzthiazepin-3-one which is dehydrogenated as described in Example 3 to form the title compound.

This l,2-dihydro compound is also obtained from the sulphoxide obtained in Example 4, by the action of H O -HCOO l-l as described in Example 5.

EXAMPLES 6 T0 29 Employing the procedure described in Examples 1 or 3, but substituting the starting material shown in the left hand column of Table I below, the product shown in the right hand column is obtained. In Table l, A can be S, 0, S0 or $0,.

1 ,Z-dihydro-l 1- Table l-(unlinucd Starting mzilvrinl Product Example No.:

14 n 0 I Aqniz CH N CH H mcmcoofl V 15 -CH2 A-CI-Iz fil @0113 Iiaorfi @CH -C2H5 -02 CH N CH CH mcmooon Q A-cn} A- H,

[ 11 SCZH5 -SCH -CH N/ H OH\N 5 mcmcoon V 17 A-CH; A-CH;

OH CH l CI-hCHaC 0 O H 1 0 1s A-CH1 A-CH;

O G 41 @431 g n Q CH mcmcoofi l\) 19 A-cn, V A-CH1 O 0 3 CH 1 1 CH cu 'cmcmc 00H id 20 A-cn, A-CQ:

CH1 CH3 0 0 -01 @C] CH N CH CH mcmc 0 on O Table l-(untinucd Starting material Product,

Example No.:

' 21 A-CH1 21-021,

01 C) 0 01 O on N 011 CH mcmooon L) A-cH,

CH\N

22 A-cm A-cn,

CH\N/ CH CH mcmooofi U 23 A-cH, A-CH1 c1 0 0 --CF; 01 9 CF CH N CH CH c mcmcoon L) 24 A-CH: A-CHa HsCr-(QT G C4Hn H5Cr@ EC:

CH\N/ CH CH 21s A-Clh A cn,

CH\N/ CH CH mcmooon U A-cm A cH,

on N CH CH 27 A A-CH: A-CH:

011 on HO O G sow 1H Q wu J n1' g a CH\N/ ('11 1 (1 1 02H! N (3 115 (5111011100011 U Table l-(onlinucd Starting m utvrinl Product Example No.1

EXAMPLES 30 TO 36 Employing the Procedure of Examole l, but substituting the 5,1 l-dihydrodibenz[b,e][ l,4]oxa(or thia)ze- V .\cI-I,

olmofil I 34:

CH N on J OM50 6 CN pom L CH pine shown in Column 1 of Table I] below and th nitrile shown in Column 2, the product shown in Column 3 is obtained.

TABLE II Column 1 Column 2 Column 3 Example No.:

30 A-CH; CH GHC N A--CH O O 0 F 6 F30 CH N CH CH N A--CH CH CH-C N A-CH;

N019 H N ,H

32 l. A-CH /NO2S H 1130 CH 33 A--CH;

H N OH 34 A--CH;

TABLE II unllnucrl Column 1 Column .2 (nlumn 3 Example N;

a r V c :\CH7 CHQICH (:N -I

me m0 O O C) 01 (1 a CH N CH cii 36 ACH2 CH CH C N What is claimed is: l. A compound of the structure:

4. A compound in accordance with claim 1 having the structure A-CH:

t Lo

5. A compound in accordance with claim I having )n (Y)n' I t he struc ure 3. A compound in accordance with claim 1 having the structure 6. A compound in accordance with claim l having the structure I Inventofls) m :L: is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below- Column 1, line 3 "thialzepin should -read: thia) zepin Dated September 18, 1973 Harry L. Yale and Ramesh B. Petigara Column 3 formulad7, that portion of the formula reading:

Column Column Column Column I LKL O should read:

CH C H line 4 "2-bromacrylonitrile, should read: 2-bromoacrylonitrile,

line 52, "Med. Chem." should read J Med. Chem.

line"58, "so" should read: SO

formula 3', that portion of the formula] reading: "A=CH should read: A-CH line 33, "[b,e]]l,4]" should read: [b,e] [1,4

Example 7, Product Column, that portion of the formula reading: v

n ll V i 7 Should read: I a QC OCH UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Page 2 2:0. 3,759,923 Dated September 18 1973 Inventor) Harry L.. Yale and Ramesh B. Petigara It is certified that error appears in the above-id v entifi' d ato and cant said Letters Patent are hereby corrected as L p shown below:

Column 20, 1 Example 9,

reading:

" @CH V should read: IZDDCH Product Column, that portion of the formula Column 20, Example 10, Product Column,

that portion of the formula reading:

. v CH should read:

Column 22 Example 15, Product Column, that portion of the formula reading:

n CH II hould read: Ell-CH a c 2 5 Column 24, Example 24, Product Column, that portion of the formula reading: I

Column 26, Example 29, Product Columny that portion of the formula reading:

(Q h uld read:

CH c a CH Cl Signed and sealed this 16th day of July 1974.

(SEAL) Attest:

MCCOY M. GIBSON, JR. c. MARSHALL DANN Attesting Officer Commissioner of Patents 

2. A compound in accordance with claim 1 having the structure
 3. A compound in accordance with claim 1 having the structure
 4. A compound in accordance with claim 1 having the structure
 5. A compound in accordance with claim 1 having the structure
 6. A compound in accordance with claim 1 having the structure 